Jonathan P. Moore

Benefits of exercise in Rheumatoid Arthritis.

This paper aims to highlight the importance of exercise in patients with rheumatoid arthritis (RA) and to demonstrate the multitude of beneficial effects that properly designed exercise training has in this population. RA is a chronic, systemic, autoimmune disease characterised by decrements to joint health including joint pain and inflammation, fatigue, increased incidence and progression of cardiovascular disease, and accelerated loss of muscle mass, that is, “rheumatoid cachexia”. These factors contribute to functional limitation, disability, comorbidities, and reduced quality of life. Exercise training for RA patients has been shown to be efficacious in reversing cachexia and substantially improving function without exacerbating disease activity and is likely to reduce cardiovascular risk. Thus, all RA patients should be encouraged to include aerobic and resistance exercise training as part of routine care. Understanding the perceptions of RA patients and health professionals to exercise is key to patients initiating and adhering to effective exercise training.

Cerebrovascular responses to hypoxia and hypocapnia in high-altitude dwellers

Cerebral blood flow is known to increase in response to hypoxia and to decrease with hypocapnia. It is not known, however, whether these responses are altered in high‐altitude dwellers who are not only chronically hypoxic and hypocapnic, but also polycythaemic. Here we examined cerebral blood flow responses to hypoxia and hypocapnia, separately and together, in Andean high‐altitude dwellers, including some with chronic mountain sickness (CMS), which is characterized by excessive polycythaemia. Studies were carried out at high altitude (Cerro de Pasco (CP), Peru; barometric pressure (PB) 450 mmHg) and repeated, following relief of the hypoxia, on the day following arrival at sea level (Lima, Peru; PB 755 mmHg). We compared these results with those from eight sea‐level residents studied at sea level. In nine high‐altitude normal subjects (HA) and nine CMS patients, we recorded middle cerebral artery mean blood flow velocity (MCAVm) using transcranial Doppler ultrasonography, and expressed responses as changes from baseline. MCAVm responses to hypoxia were determined by changing end‐tidal partial pressure of oxygen (PET,O2) from 100 to 50 mmHg, with end‐tidal partial pressure of carbon dioxide clamped. MCAVm responses to hypocapnia were studied by voluntary hyperventilation with (PET,O2) clamped at 100 and 50 mmHg. There were no significant differences between the cerebrovascular responses of the two groups to any of the interventions at either location. In both groups, the MCAVm responses to hypoxia were significantly greater at Lima than at CP (HA, 12.1 ± 1.3 and 6.1 ± 1.0%; CMS, 12.5 ± 0.8 and 5.6 ± 1.2%; P < 0.01 both groups). The responses at Lima were similar to those in the sea‐level subjects (13.6 ± 2.3%). The responses to normoxic hypocapnia in the altitude subjects were also similar at both locations and greater than those in sea‐level residents. During hypoxia, both high‐altitude groups showed responses to hypocapnia that were significantly smaller at Lima than at CP (HA, 2.17 ± 0.23 and 3.29 ± 0.34% mmHg−1, P < 0.05; CMS, 1.87 ± 0.16 and 3.23 ± 0.24% mmHg−1; P < 0.01). The similarity of the results from the two groups of altitude dwellers suggests that haematocrit is unlikely to greatly affect cerebrovascular reactivity to hypoxia and hypocapnia. The smaller vasodilatation to hypoxia and larger vasoconstriction to hypoxic hypocapnia at high altitude suggest that cerebrovascular responses may be impaired at the high altitude, i.e. a maladaptation. The changes in the responses within less than 24 h at sea level indicate that this impairment is rapidly reversible.

Central nucleus of amygdala projections to rostral ventrolateral medulla neurones activated by decreased blood pressure.

The central nucleus of amygdala (CeA) participates in cardiovascular regulation during emotional behaviour but it has not been established whether any of these effects are mediated through its direct connections to blood pressure‐regulating neurones in the rostral ventrolateral medulla (RVLM). The RVLM contains barosensitive neurones that maintain resting blood pressure via their projections to sympathetic preganglionic neurones in the thoracic spinal cord. In this study on rats, we used combined anterograde neuronal tracing of CeA projections with confocal and electron microscopic immunohistochemical detection of phenylethanolamine‐N‐methyltransferase, the adrenaline‐synthesizing enzyme present in C1 catecholamine neurones of the RVLM, and Fos, the protein product of the c‐fos proto‐oncogene. Fos expression in barosensitive neurones was stimulated by an intravenous infusion of the hypotensive agent sodium nitroprusside. Injection of the tracer biotin dextran amine (10‐kDa form) into the CeA resulted in anterograde labelling of axons and varicosities throughout the RVLM without retrograde labelling of somata in any brain area. With confocal microscopy, presumptive CeA terminals were found in close apposition to adrenergic (phenylethanolamine‐N‐methyltransferase‐immunoreactive) and non‐adrenergic neurones that displayed Fos‐immunoreactive nuclei in response to decreased blood pressure. Electron microscopic analysis confirmed that some labelled terminals of CeA axons made synaptic contact with c‐fos‐activated adrenergic neurones. The results provide evidence that cardiovascular influences elicited from the CeA during stressful events may be mediated, at least in part, via monosynaptic neural projections to barosensitive sympathetic blood pressure‐regulating neurones in the RVLM.

Orthostatic tolerance and blood volumes in Andean high altitude dwellers

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head‐up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

Pulmonary arterial distension and vagal afferent nerve activity in anaesthetized dogs

Distension of the main pulmonary artery and its bifurcation are known to result in a reflex vasoconstriction and increased respiratory drive; however, these responses are observed at abnormally high distending pressures. In this study we recorded afferent activity from pulmonary arterial baroreceptors to investigate their stimulus–response characteristics and to determine whether they are influenced by physiological changes in intrathoracic pressure. In chloralose‐anaesthetized dogs, a cardiopulmonary bypass was established, the pulmonary trunk and its main branches were vascularly isolated and perfused with venous blood at pulstatile pressures designed to simulate the normal pulmonary arterial pressure waveform. Afferent slips of a cervical vagus were dissected and nerve fibres identified that displayed discharge patterns with characteristics expected from pulmonary arterial baroreceptors. Recordings were obtained with (a) chest open (b) chest closed and resealed, and (c) with phasic negative intrathoracic pressures in the resealed chest. Pressure–discharge characteristics obtained in the open‐chest animals indicated that the threshold pulmonary pressure (corresponding to 5% of the overall response) was 17.1 ± 2.9 and the inflexion point of the curve was 29.2 ± 3.3 mmHg (mean ±s.e.m). In closed‐chest animals the threshold and inflexion pressures were reduced to 12.0 ± 1.7 and 20.7 ± 1.8 mmHg. Application of phasic negative intrathoracic pressures further reduced the threshold and inflexion pressures to 9.5 ± 1.2 mmHg (P < 0.05 vs. open) and 14.7 ± 0.8 mmHg (P < 0.003 vs. open and P < 0.02 vs. atmospheric). These results indicate that under physiological conditions, with closed‐chest and phasic negative intrathoracic pressure changes similar to those associated with normal breathing, activity from pulmonary baroreceptors is obtained at physiological pulmonary arterial pressures in intact animals.

Afferent discharges from coronary arterial and ventricular receptors in anaesthetized dogs.

1. Previous work has shown that increases in aortic root pressure result in reflex vasodilation, and that this response is likely to result mainly from stimulation of receptors in the coronary arteries, although contribution from left ventricular receptors was not excluded. This investigation was undertaken to resolve this question and to determine the afferent nerve fibres likely to be involved in this reflex. 2. In chloralose‐anaesthetized dogs a perfusion circuit was used which allowed us to change the pressures in: (a) the aortic root, coronary arteries and the left ventricle; (b) aortic root and coronary arteries at constant ventricular pressure; and (c) the left ventricle with mean (although not pulse) aortic pressure constant. Electrophysiological recordings were made from slips dissected from the vagus nerve which responded with an increase in discharge to either combined increases in the pressures, or to aortic root injections of veratridine. 3. Recordings were made from twenty‐one vagal afferents. On the basis of their conduction velocities, eleven were classified as non‐myelinated and ten as myelinated. 4. Three non‐myelinated afferents responded to veratridine injections only, three to both veratridine and combined aortic root and ventricular pressure changes, and five to pressure changes only. Responses to pressure occurred only when ventricular systolic pressure exceeded 30 kPa. 5. None of the myelinated afferents responded to veratridine. All showed increases in discharge to combined increases in mean aortic root, coronary arterial and left ventricular systolic pressures, which would be graded over a range similar to that which caused reflex changes. All were more sensitive to changes in mean coronary pressure than to changes in ventricular systolic pressure. 6. We conclude that myelinated vagal afferent nerve fibres, which respond predominantly to changes in mean coronary arterial pressure, are likely to be responsible for the vasodilation to the changes in mean aortic root pressure previously reported. These fibres are probably attached to coronary arterial mechanoreceptors.

Heat acclimation responses of an ultra-endurance running group preparing for hot desert-based competition

Abstract Heat acclimation induces adaptations that improve exercise tolerance in hot conditions. Here we report novel findings into the effects of ultra-marathon specific exercise load in increasing hot ambient conditions on indices of heat acclimation. Six male ultra-endurance runners completed a standard pre-acclimation protocol at 20°C ambient temperature (T amb), followed by a heat acclimation protocol consisting of six 2 h running exercise-heat exposures (EH) at 60% O2max on a motorised treadmill in an environmental chamber. Three EH were performed at 30°C T amb, followed by another three EH at 35°C T amb. EH were separated by 48 h within T amb and 72 h between T amb. Nude body mass (NBM), blood and urine samples were collected pre-exercise; while NBM and urine were collected post-exercise. Rectal temperature (T re), heart rate (HR), thermal comfort rating (TCR) and rating of perceived exertion were measured pre-exercise and monitored every 5 min during exercise. Water was provided ad libitum during exercise. Data were analysed using a repeated measures and one-way analysis of variance (ANOVA), with post hoc Tukeys HSD. Significance was accepted as P< 0.05. Overall mean T re was significantly lower during 30°C EH3 and 35°C EH3 compared with their respective EH1 (−0.20 and−0.23°C, respectively; P<0.05). Similarly, overall mean HR was significantly lower during 30°C EH3 and 35°C EH3 compared with their respective EH1 (8 and 7 bpm respectively; P<0.05). A significant decrease in overall mean TCR was observed during 35°C EH3, compared with 35°C EH1 (P< 0.05). Significant increases in resting pre-exercise plasma volume (estimated from Hb and Hct) were observed by 30°C EH3 (7.9%; P< 0.05). Thereafter, plasma volume remained above baseline throughout the experimental protocol. Two EH of 2 h at 60% O2max at 30°C T amb was sufficient to initiate heat acclimation in all ultra-endurance runners. Further, heat acclimation responses occurred with increasing EH to 35°C T amb. Preventing exertional heat illnesses and optimising performance outcomes in ultra-endurance runners may occur with exposure to at least 2 h of exercise-heat stress on at least two occasions in the days leading up to multi-stage ultra-marathon competition in the heat.

Cardiovascular responses to orthostatic stress in healthy altitude dwellers, and altitude residents with chronic mountain sickness

High altitude (HA) dwellers have an exceptionally high tolerance to orthostatic stress, and this may partly be related to their high packed cell and blood volumes. However, it is not known whether their orthostatic tolerance would be changed after relief of the altitude‐related hypoxia. Furthermore, orthostatic tolerance is known also to be influenced by the efficiency of the control of peripheral vascular resistance and by the effectiveness of cerebral autoregulation and these have not been reported in HA dwellers. In this study we examined plasma volume, orthostatic tolerance and peripheral vascular and cerebrovascular responses to orthostatic stress in HA dwellers, including some with chronic mountain sickness (CMS) in whom packed cell and blood volumes are particularly large. Eleven HA control subjects and 11 CMS patients underwent orthostatic stress testing, comprising head‐up tilting with lower body suction, at their resident altitude (4338 m) and at sea level. Blood pressure (Portapres), heart rate (ECG), brachial and middle cerebral artery blood velocities (Doppler) were recorded during the test. Plasma volumes were found to be similar in both groups and at both locations. Packed cell and blood volumes were higher in CMS patients than controls. All subjects had very good orthostatic tolerances at both locations, compared to previously published data in lowland dwellers. In CMS patients responses of forearm vascular resistance to the orthostatic stress, at sea level, were smaller than controls (P < 0.05). Cerebral blood velocity was less in CMS than in controls (P < 0.01) and, at sea level, it decreased more than the controls in response to head‐up tilting (P < 0.02). Cerebral autoregulation, assessed from the relationship between cerebral pressure and velocity, was also impaired in CMS patients compared to HA controls, when examined at sea level (P < 0.02). These results have shown that the good orthostatic tolerance seen in high altitude dwellers at altitude is also seen at sea level. There was no difference in orthostatic tolerance between CMS patients, with their exceptionally large blood volumes, and the HA controls. This may be because peripheral vascular and cerebrovascular responses (at least at sea level) are impaired in the CMS patients relative to HA controls. Thus, the advantage of the large blood volume may be offset by the smaller vascular responses.

Phasic negative intrathoracic pressures enhance the vascular responses to stimulation of pulmonary arterial baroreceptors in closed‐chest anaesthetized dogs

We investigated whether the reflex responses to stimulation of pulmonary arterial baroreceptors were altered by intrathoracic pressure changes similar to those encountered during normal breathing. Dogs were anaesthetized with α‐chloralose, a cardiopulmonary bypass was established, and the pulmonary trunk and its main branches as far as the first lobar arteries were vascularly isolated and perfused with venous blood. The chest was closed following connection to the perfusion circuit and pressures distending the aortic arch, carotid sinus and coronary artery baroreceptors were controlled. Changes in the descending aortic (systemic) perfusion pressure (SPP; flow constant) were used to assess changes in systemic vascular resistance. Values of SPP were plotted against mean pulmonary arterial pressure (PAP) and sigmoid functions applied. From these curves we derived the threshold pressures (corresponding to 5% of the overall response of SPP), the maximum slopes (equivalent to peak gain) and the corresponding PAP (equivalent to ‘set point’). Stimulus–response curves were compared between data obtained with intrathoracic pressure at atmospheric and with a phasic intrathoracic pressure ranging from atmospheric to around −10 mmHg (18 cycles min−1). Results were obtained from seven dogs and are given as means ±s.e.m. Compared to the values obtained when intrathoracic pressure was at atmospheric, the phasic intrathoracic pressure decreased the pulmonary arterial threshold pressure in five dogs; average change from 28.4 ± 5.9 to 19.3 ± 5.9 mmHg (P > 0.05). The inflexion pressure was significantly reduced from 37.8 ± 4.8 to 27.4 ± 4.0 mmHg (P < 0.03), but the slopes of the curves were not consistently changed. These results have shown that a phasic intrathoracic pressure, which simulates respiratory oscillations, displaces the stimulus–response curve of the pulmonary arterial baroreceptors to lower pressures so that it lies within a physiological range of pressures.

The membrane properties and firing characteristics of rat jaw-elevator motoneurones.

1. We have determined the membrane and firing properties of fifty‐six jaw‐elevator motoneurones in rats that were anaesthetized with pentobarbitone, paralysed and artificially ventilated. 2. Forty‐two neurones were identified as masseter motoneurones and fourteen as masseter synergist motoneurones. The membrane potentials for the sample ranged from ‐60 to ‐86 (mean = ‐68; S.D. = 7.3; n = 56), and spike amplitudes from 50 to 95 mV. The duration of the after‐hyperpolarization following antidromic spikes in masseter motoneurones ranged from 15 to 50 ms (mean = 30; S.D. = 12.8) and their amplitudes from 1.0 to 4.5 mV (mean = 2.7; S.D. = 2.2; n = 42). 3. The mean input resistance for the total sample was 2.3 M omega (S.D. = 0.9; n = 56), membrane time constant 3.9 ms (S.D. = 0.9; n = 48) and rheobase 4.2 nA (S.D. = 2.6; n = 56). The distribution of these parameters was independent of membrane potential. We found no significant interrelationships between the membrane properties and one interpretation of this is that our sample may be drawn from a homogenous population of motoneurones. We also suggest that elevator motoneurones may have a lower Rm (specific membrane resistivity) value than cat hindlimb motoneurones because they have a similar range of input resistance values but only half the total surface area. 4. Forty‐six out of forty‐nine neurones fired repetitively to a depolarizing current pulse at a mean threshold of 1.6 x rheobase. Current‐frequency plots were constructed for thirteen neurones and all but one showed a primary and secondary range in the firing of the first interspike interval. The mean slope in the primary range was 31 impulses s‐1 nA‐1 and 77 impulses s‐1 nA‐1 for the secondary range. The mean minimal firing frequency for steady firing was 26 impulses s‐1 and, in response to an increase of stimulation, the rate increased monotonically with a slope of 11 impulses s‐1 nA‐1. 5. The dynamic sensitivity of twelve neurones was assessed from their response to ramp waveforms of current of constant amplitude but varying frequencies (0.2‐2 Hz). Firing initially increased along a steep slope up to a frequency of between 40 and 60 impulses s‐1 and then increased along a much shallower slope. Both the threshold for eliciting firing and the firing at the transition point of the two slopes remained constant with changes in ramp frequency.(ABSTRACT TRUNCATED AT 400 WORDS)